Post-stroke depression (PSD) is the most common psychiatric complication of stroke (Shi et al., 2021; Chen et al., 2020). The incidence of PSD is high within the 1st year after stroke (Towfighi, et al., 2017). PSD not only influences recovery of the stroke patients, but also prolongs the stay with increased treatment costs, these brings a heavy burden on their families (Zhou et al., 2022). Moreover, the mortality rate of patients with PSD is much higher than the patients with stroke alone (Guo et al., 2022). Accumulated evidence demonstrate that post-stroke depression is different from major depressive disorder (MDD) in many ways (Dayuan et al., 2022; Blake et al., 2023). The most noticeable difference between PSD and MDD is that approximately 30% of PSD patients fail to respond to antidepressant medicines (Fruehwald et al., 2003; Mortensen and Andersen, 2021). Consequently, it is rather necessary to uncover the pathophysiology of PSD and develop feasible strategies for prevention and treatment.

Social interaction (SI), also known as social contact or social interaction, is manifested as group rearing in experimental animals (Norman et al., 2010). Clinical studies have found that social interaction is beneficial to stroke rehabilitation (Bosch and Young, 2018), and mitigates neuroinflammation after focal cerebral ischemia (DeVries et al., 2007). Preclinical findings have shown that social interaction significantly reduces infarct size and attenuates depression-like behaviors (Verma et al., 2014; Zheng et al., 2014). However, the underlying mechanisms remain unclear. In our previous study, we have found disturbances in gut are involved in depressive contagion between PSD mice and their healthy partners, there is significant change in short-chain fatty acids (SCFAs), which are derived from gut microbiota (Wang et al., 2023a). Thereby, these fascinating results prompt that gut microbiota may be associated with the protection of pair housing against PSD.

There is a bidirectional regulation between the gut and brain (Oroojzadeh et al., 2022). Increasing studies have demonstrated that gut microbiota has a powerful influence on mood, behavior, and cognitive function et al. (Osadchiy et al., 2019; Agirman et al., 2021). The exchange of information among gut microbiota, gut and brain, is named as the microbe-gut-brain axis (Cryan et al., 2019). Depression is closely related to the gut microbiota (Liang et al., 2022), and disturbances in microbiota-gut-brain axis are involved in the progress of depression. While improvement in microbiota-gut-brain axis disorders can alleviate depression (Liang et al., 2018). Coprophagia (consumption of feces), a behavior in rodents and other animal species, has a crucial role in modulating gut microbiota. It not only contributes to nutrient intake, but also can alter the diversity of gut microbiota in rodents (Groen et al., 2006; Bo et al., 2020; Bogatyrev et al., 2020). Moreover, blocking coprophagia could increase inflammation and contribute to the development of depression in healthy mice, while transplantation the fecal microbiota from depressed donors into the healthy mice could exacerbate neuroinflammation and depression-like behaviors (Sha et al., 2023). Whether the protective effect of pair-housing on PSD correlates with disturbances in microbe-gut-brain axis remains unclear.

In the present study, we aimed to reveal the relationship between microbe-gut-brain axis and the protective effect of pair-housing on PSD. We subjected adult male C57BL/6 mice to the PSD model induced by middle cerebral artery occlusion, followed by isolated housing and restraint stress. Then, each PSD mouse was pair-housed with a male healthy partner for four weeks. While the other pair-housing mice were treated with antibiotics for four weeks. Finally, we assessed the depression-like behaviors, disorders in gut microbiota, and changes in the gut and brain.